US3609159A - 5-phenyl-2-cyclopropylamino-4-oxazolinone, and process for making the same - Google Patents
5-phenyl-2-cyclopropylamino-4-oxazolinone, and process for making the same Download PDFInfo
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- US3609159A US3609159A US655002A US3609159DA US3609159A US 3609159 A US3609159 A US 3609159A US 655002 A US655002 A US 655002A US 3609159D A US3609159D A US 3609159DA US 3609159 A US3609159 A US 3609159A
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- phenyl
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- oxazolinone
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- cyclopropylamino
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- 238000000034 method Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- -1 aryl radicals Chemical class 0.000 description 38
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 34
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- 239000002253 acid Substances 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- 238000010992 reflux Methods 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- UPULOMQHYQDNNT-UHFFFAOYSA-N 5H-1,3-oxazol-2-one Chemical class O=C1OCC=N1 UPULOMQHYQDNNT-UHFFFAOYSA-N 0.000 description 10
- 210000003169 Central Nervous System Anatomy 0.000 description 10
- BJOIZNZVOZKDIG-MDEJGZGSSA-N Reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 10
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- 238000004458 analytical method Methods 0.000 description 10
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- 125000002723 alicyclic group Chemical group 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 8
- 230000002891 anorexigenic Effects 0.000 description 8
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- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- 230000003389 potentiating Effects 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000001225 therapeutic Effects 0.000 description 8
- PGXWBZJYJBAVKD-UHFFFAOYSA-N 3-amino-1,3-oxazol-2-one Chemical class NN1C=COC1=O PGXWBZJYJBAVKD-UHFFFAOYSA-N 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 125000004429 atoms Chemical group 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229960000632 dexamfetamine Drugs 0.000 description 6
- 239000008079 hexane Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000000021 stimulant Substances 0.000 description 6
- 230000004936 stimulating Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- SMVDKGIFCLUGKH-UHFFFAOYSA-N C1(CC1)NN1C(OC=C1)=O Chemical compound C1(CC1)NN1C(OC=C1)=O SMVDKGIFCLUGKH-UHFFFAOYSA-N 0.000 description 4
- 229920001429 Chelating resin Polymers 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000002830 appetite depressant Substances 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
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- 229940079593 drugs Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- MQBHQCAEEIVRMO-UHFFFAOYSA-N 1-cyclopropyl-1-methylurea Chemical compound NC(=O)N(C)C1CC1 MQBHQCAEEIVRMO-UHFFFAOYSA-N 0.000 description 2
- FGEAOSXMQZWHIQ-UHFFFAOYSA-N 2-chloro-2-phenylacetyl chloride Chemical compound ClC(=O)C(Cl)C1=CC=CC=C1 FGEAOSXMQZWHIQ-UHFFFAOYSA-N 0.000 description 2
- OKDGPOCKHMGDQY-UHFFFAOYSA-N 3,4-dihydropyrrol-2-one Chemical compound O=C1CCC=N1 OKDGPOCKHMGDQY-UHFFFAOYSA-N 0.000 description 2
- NXQJDVBMMRCKQG-UHFFFAOYSA-N 5-phenylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)NC1C1=CC=CC=C1 NXQJDVBMMRCKQG-UHFFFAOYSA-N 0.000 description 2
- 229940025084 Amphetamine Drugs 0.000 description 2
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- 206010003549 Asthenia Diseases 0.000 description 2
- PDNSUNCBVOLHQU-UHFFFAOYSA-N C1(CC1)NC(=O)NC(C(Cl)C1=CC=CC=C1)=O Chemical compound C1(CC1)NC(=O)NC(C(Cl)C1=CC=CC=C1)=O PDNSUNCBVOLHQU-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 2
- 206010058667 Oral toxicity Diseases 0.000 description 2
- 229960004063 Propylene glycol Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
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- OIQPTROHQCGFEF-QIKYXUGXSA-L Sunset Yellow FCF Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-QIKYXUGXSA-L 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229960002734 amfetamine Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000578 anorexic Effects 0.000 description 2
- 230000002929 anti-fatigue Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
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- 230000000271 cardiovascular Effects 0.000 description 2
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- 229940023913 cation exchange resins Drugs 0.000 description 2
- 239000003576 central nervous system agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- CLMGCKCDSPUQEE-UHFFFAOYSA-N cyclopropylurea Chemical compound NC(=O)NC1CC1 CLMGCKCDSPUQEE-UHFFFAOYSA-N 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 230000000881 depressing Effects 0.000 description 2
- 150000005195 diethylbenzenes Chemical class 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000003340 mental Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 231100000418 oral toxicity Toxicity 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006308 propyl amino group Chemical group 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 230000003236 psychic Effects 0.000 description 2
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- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000002269 spontaneous Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
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- 229940078499 tricalcium phosphate Drugs 0.000 description 2
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- 238000002211 ultraviolet spectrum Methods 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
New 5-aryl-2-cycloalkylamino-4-oxazolinones of the formula:
D R A W I N G
D R A W I N G
Description
United States Patent [111 3,609,159
[ 1 Inventors Don Pierre Guidicelli 3,037,990 6/1962 l-lardy et a1, 260/307 Val de Marne; 3,047,461 7/1962 Hardy et a1. 260/307 Henry Naier, Paris, both of France [21] Appl. No. 655,002
[22] Filed July 21, 1967 [45] Patented Sept. 28, 1971 [73] Assignee Les Laboratoires Dausse Paris, France [32] Priority Mar. 1, 1963,Mar. 15, 1963, Sept. 24,
[33] France [311 926,545, 928,067 and 32,611
Continuation-impart of application Ser. No. 580,908, Sept. 21, 1966, now abandoned Continuation-impart of application Ser. No. 348,296, Feb. 28, 1964, now abandoned.
[54] 5-PHENYL-2-CYCLOPROPYLAMlNO-4- OXAZOLINONE, AND PROCESS FOR MAKING THE SAME 2 Claims, No Drawings [52] U.S. Cl 260/307 A,
260/544 M, 260/553 E, 424/272 [51] Int. Cl C07d 85/30 [50] Field of Search ..260/307 (1) [56] References Cited UNITED STATES PATENTS 2,892,753 6/1959 Schmidt et a1. 260/307 3,029,189 4/1962 Hardy et a1. 260/307 OTHER REFERENCES Najer et al., Bull. Soc. Chim. France, Ser. 5, pages 1810- 1813 (1963).
Primary Examiner-Alton D. Rollins Attorney-Stevens, Davis, Miller & Mosher ABSTRACT: New 5-aryl-2-cycloalkylamino-4-oxazolinones of the formula:
in the form of racemate or optical isomer and its acid addition salts, wherein R., R R R and R, are each hydrogen. halogen, trifluoromethyl, lower alkyl, lower alkoxy. amino. amino substituted by one or two alkyl. cycloalkyl or aryl radicals, or by an aliphatic, alicyclic or aromatic acyl radical. an aliphatic, alicyclic or aromatic acyl radical. alkylmercapto. sulphonamido, monoor di-substituted sulphonamido. cyano, or a substituted or unsubstituted carbamoyl radical; n is l. 2. 3 or 4; and R is hydrogen, lower alkyl. cycloalkyl. or lower w-hydroxyalkyl are useful as stimulants of the central nervous system and as anorexic agents.
-PHENYL-2-CYCLOPROPYLAMINO-4-OXAZOLINONE, AND PROCESS FOR MAKING THE SAME These compounds may be prepared by cyclizing a compound of the formula:
in which Hal denotes a halogen atom, more especially a chlorine atom, and R, R R2, R3, R and R5 are as aforesaid, the cyclization being effected by heating the said urea compound in the presence of the calculated amount of sodium alcoholate or other suitable hydrogen halide acceptor.
This application is a continuation-in-part of copending applications Ser. No. 348,296 filed Feb. 28, 1964, and Ser. No. 580,908, filed Sept. 21, 1966, and both now abandoned.
This invention relates to new compounds, their preparation and pharmaceutical compositions containing the same, more particularly to new oxazolinones which, as stimulants of the central nervous system and anorexic agents, are unexpectedly more potent than the 5-phenyl-2-unsubstituted and substituted amino-4-oxazolinones heretofor proposed for these purposes.
The present invention provides, as new compounds in both racemic and optically active forms, the oxazolinones of the formula and their acid addition salts, wherein R R R R, and R are each hydrogen, halogen (such as chlorine, bromine, iodine or fluorine), trifluoromethyl, lower alkyl, lower alkoxy, amino, amino substituted by one or two alkyl, cycloalkyl, or aryl radicals, or by an aliphatic, alicyclic or aromatic acyl radical, an aliphatic, alicyclic or aromatic acyl radical, alkylmercapto, sulfonamido, monoor disubstituted sulfonamido, cyano, or a substituted or unsubstituted carbamoyl radical; n is l, 2, 3 or b 4; and R is hydrogen, lower alkyl, cycloalkyl, or lower tohydroxy-alkyl.
Especially valuable compounds of formula 1 are those in which R, R R R and R are each hydrogen, halogen or lower alkyl, R is hydrogen or lower alkyl, and n is l, 2, 3, or 4.
The new oxazolinones may be prepared by cyclizing a urea compound of the formula:
R Rr I -Qa r 01 NH R4 R5 RN-CH CH II The starting material of formula 11 may be prepared by condensing an a-aryl-a-chloracetyl chloride of formula III with a urea of formula IV, the symbols being as defined above, in accordance with the following reaction scheme:
1 I f 2)n l C1 C1 CH2 R4 5 III IV conventional manner, bearing in mind that those compounds in which n=l are somewhat sensitive to acid, and that it is necessary in such cases to insure that the cyclopropyl ring is not destroyed by the action of the acid. This may be done, for example, by preparing the salt in an inert anhydrous medium, such as diethyl ether or benzene. The base and the appropriate acid are mixed together in stoichiometric proportions, and the acid addition salt isolated in the usual manner.
The invention will be further understood by the following description in which are included examples of the process for the production of these novel compounds and of the preparation and use of pharmaceutical compositions therefrom. It will be understood that the several examples are intended to be illustrative of the invention and not in any way a limitation thereof.
It is well known that 5-phenyl-2-amino-4-oxazolinone is a stimulant for the central nervous system, and that a few Nsubstituted derivatives thereof are more powerful stimulants than said 5-phenyl-2-amino-4-oxazolinone, to wit in the order of decreasing activities, the 2monoethylamino, 2- monomethylamino and 2-dimethylamino derivatives. It is further known that in the 2-monoalkylamino derivative series, the activity decreases very quickly from 2 carbon atoms in the alkyl group upwards and eventually is reversed. More particularly the n-monopropylamino derivative shows but a very low activity and the monoisopropylamino compound shows no activity.
It was thus quite unexpected to find that although having a 3-carb0n atom group attached to the nitrogen atom in the 2- position, a 5-phenyl-2-mono-substituted amino-4-oxazolinone is definitely more potent than all above named, stimulating compounds.
EXAMPLE I a. N -cyclopropyl-N'-(alpha-phenyl-alpha-chloro-acetyl) urea:
Into a three-necked spherical flask having a capacity of 1 liter and provided with a dropping funnel, a condenser surmounted by a calcium chloride tube and a mechanical stirrer, there were suspended 17.6 g. (0.176 g.-mol) of cyclopropylurea and 21.3 g. (0.176 g.-mol) of dimethylaniline in 310 ml. of anhydrous benzene. While stirring, there was added through the dropping funnel in 45 minutes a solution of 33.3 g. (0.176 g.-mol) of alpha-phenyl-alpha-chloroacetyl chloride in 130 ml. of anhydrous benzene. The mixture was then left at ambient temperature with stirring for 1 hour then heated under reflux on the water bath with stirring for 5 hours.
The benzene solution was decanted while still warm and thereby separated from an oil deposited on the flask wall, the benzene was evaporated on the water bath in vacuo, the oily residue was triturated 3 successive times in ml. of ether, ether being decanted each time, the last traces of ether were removed in vacuo, then the oil was triturated in 250 ml. of water until it crystallized. The crystalline precipitate was filtered off, copiously washed with water and dried in vacuo over phosphorus pentoxide.
There were thus recovered 24.7 g. (yield 55 percent) of N cyclopropyl- N (alpha phenyl alpha chloroacetyl) urea which, when recrystallized from 400 ml. of a mixture of ethyl TABLE 1 alcohol and hexane (1 4), had a melting point of 134l 35 5 'f 8 Dumb" C oxazohnone gJkg. intensity of duration compound (i.p.) of motive maximum of Analysis C H ClN 02 (M01 weight 252.5) "citation activity admin percent calc. C 57.03 H 5.15 Cl 14.05 N 11.09 (minutes) (hours) percentfound 56.88 5.09 13.33 11.16
10 Z-monocycltr from +H- 120-180 6 b. 5-phenyl-2-monocyclopropylamino-4-oxazolinone. propylamino 0.01 w 16.6 g. (0.066 g.-mol.) of this N -cyclopropyl-N"- alphaizrjf 6 phenyl-alpha-chloroacetyl)-urea was dissolved in a sodium zqnonwhyb 3M0 how 3 ethoxide solution containing 1.5 g. (0.066 g.-atom) of sodium amino 0.01 to in 330 ml. of absolute ethyl alcohol, and the mixture was y 120-180 0 heated under reflux for 2 hours. The precipitated sodium f chloride was filtered ofi, alcohol was evaporated from the fil- 3:21 0 05 I? I; trate on the water bath in vacuo, the gummy residue was tritu- Comm rated in 150 ml. of water until it crystallized, and the compound was filtered off, copiously washed with water and dried in vacuo over phosphorus pentoxide.
There were recovered 11.4 g. (yield 80 percent) of S-pheniz ffiizw t h i "T grates! mom: yl-2-monocyclopropylamino-4-oxazolinone which, when a m es e F recrystallized from 500 ml. of a mixture of ethyl alcohol and e same expenmem l out by admlmstenng hexane (1 :4), had a melting point of l39-140 C. p unds orally gave very similar results except as regards the UV spectrum (in ethanol): Amax; 224 MMFZSQOO) monomethylamino compound, which was inferior to the IR spectrum (in KBr): 1740 cm. c=0), 1640 cm. c mofloethylamim compound- N) The central nervous system stimulating properties of this Anal Sis C H N 0 Mo] Wei ht 216 new monocyclopropylamino 4-oxazolinone were further y 12 2 2( g demonstrated by the inhibiting effect that said compound produces towards the depressing effects of reserpine. 2:3,; C 2F H 51 N Two lots of 10 mice were given orally 0.010 gJkg. of the 66.74 5.60 -oxazolinone new compound (first lot) and 0.010 gJkg. of til-amphetamine 5.phenyl-2.monocyclop oyl3mifl0-4-() azolinone is a white (second [0!) a hil'd lot Of mic served as a control. 2 crystalline substance which is soluble in cold ethyl alcohol, inhours after the ing i n of the above substances by the soluble in water, stable in alkaline medium but unstable in anim s n th rs! t 1018, the mice in the three lots were acid medium. A suspension of the oxazolinone in boiling 1O given 0.002 gJkg. of reserpine (dissolved in a mixture of percent aqueous solution of sulfuric acid, is converted very acetic acid, propylene-glycol and water) by the inquickly to S-phenyl-oxazolidine-Z, 4-dione. 40 traperitoneal route. The animals were then observed 1 hour, 3 The corresponding Z-monoeyclobutylamino, 2-mon0- hours and 18 hours after the injection of reserpine. The results cyclopentylammo and 2-monocyclohexylamino compounds are tabulated below:
TABLE II Dosage Spontaneous activity after injecting reserpine 5- h 14-0 azolinone compound ag 0 1 hour 3 hours 18 n31";
p eny X 2-monocyclopropylamino 0.010 ptosis 8/10 ptosis 7/10. dl-Amphetamine 0. 010 ptosis 10/10 ptosis 10/10. Controls ptosis 10/10 ptosis 10/10.-- ptosis 10/10.
1 1 d 1311. 2 2 d tlis.
N oTE.i-++ strong depression; mean depression; weak depression; definite activity.
may be prepared similarly. However, when tested, these compounds exhibit no pharmacological activity whereas the 2- monocyclopropylamino compound exhibits central nervous system stimulating properties and anorexigenic properties much more potent than those of 5-phenyl-2(unsubstituted) amino-4-oxazolinone, of the various S-phenyl-Z-monoloweralkylamino-4-oxazolinones, and of 5-monocyclopropylamino-4-oxazolinone has much more favorable therapeutic index and margin of safety than the other S-phenyl-2-amino-4-oxazolinones (whether substituted or not in the amino group in the 2-position).
Observations made after injecting intraperitoneally in mice 0.01 g.lkg. of 5-phenyl-2-monocyclopropylamino-4-oxazolinone comparatively with the following known com pounds administered by the same route: 5-phenyl-2- monomethylamino-4-oxazolinone (0.05 g.lkg.), 5-phenyl-2- monoethylamino-4-oxazolinone (0.01 g./kg. and 0.05 gJkg.) and 5-phenyl-2-dimethylamino-4-oxazolinone (0.05 g./kg.), are set out in the following table:
The above table shows that S-phenyl-Z-mono cyclopropylamino-4-oxazolinone produces antidepressing effects at least equal to those caused by til-amphetamine towards the action of reserpine.
EXAMPLE ll The reaction mixture is then left for 1 hour at ambient temperature. The reaction is finished by heating under reflux for 5 hours on a water bath. The mixture is allowed to cool. An oil which has deposited on the walls of the flask is separated, the benzene is evaporated on a water bath in vacuo, the oily residue is triturated successively three times with 100 ml. of ether with decantation on each occasion, the last traces of ether are removed in vacuo, and the oil is then triturated with 250 ml. of water until it crystallizes. The crystals are filtered ofi, copiously washed with water, and the compound dried in vacuo over phosphorus pentoxide. 28.6 g. (56 percent yield) of N-cyclopropyl-N'-(a-p-chlorophenyl-a-chloroacetyl)urea are obtained. After recrystallization from isopropyl alcohol, it melts at 132 C.
Analysis for CmHuClgNgOz (M.W.
Calc. percent: C==50.18 percent l-l=4.l8 percent Cl=24.74 percent N=9.76 percent Found: @5027 percent l-l=4.07 percent C1=24.51 percent N=9.81 percent b. 5-(p-chlorophenyl)-2-cyclopropylamino-4-oxazolinone 28.7 g. (0.1 g. mole) of N-cyclopropyl-N-(a-p-chlorophenyla-chloroacetyl urea dissolved in a solution of sodium ethoxide obtained by dissolving 2.3 g. (0.1 g. atom) of sodium in 500 ml. of absolute alcohol, and the mixture is heated for 2 hours under reflux. The sodium chloride produced is filtered off, the alcohol is evaporated from the filtrate on a water bath in vacuo, the gummy residue is triturated with 250 ml. of water until it crystallizes, and the compound is filtered off, copiously washed with water and dried in vacuo over phosphorus pentoxide. 18.5 g. (64.5 percent yield) of 5-p-chlorophenyl-2- cyclopropylamino-4-oxazolinone are obtained. After recrystallization from absolute alcohol, it melts at 21 1 C.
Analysis for cflflnclNzog (M.W.=250.5)
Calc. C=57.49 percent 1-l=4.38 percent Cl=l4.l7 percent N=1 1.16 percent Found: C=57.41 percent 1-l=4.32 percent Cl=14.3 1 percent N=11.29 percent EXAMPLE lIl Preparation of 5-pheny1-2-(N-cyclopropyl-N-methylamino)-4 -oxazolinone a. ltI-cyclopropyl-N-methy1-N'-(oz-phenyl-oz-chloractyl)- urea 11.4 g. (0.1 g. mole) of N-cyclopropyl-N-methyl urea, 12.1 g. (0.1 g. mole) of dimethylaniline and 200 ml. of anhydrous benzene are introduced into a 1 liter. three-necked,
round-bottom flask provided with a dropping funnel, a mechanical stirrer, and a reflux condenser closed with a calcium chloride tube. 18.9 g. (0.1 g. mole) of a-phenyl-achloracetyl chloride in 100 ml. of anhydrous benzene are added to this suspension, which is stirred mechanically. from the dropping funnel over the course of 1 hour. The reaction mixture is left for 1 hour at room temperature, and the reaction is then completed by heating under reflux for several hours on a water bath. The mixture is allowed to cool, the supernatant liquid is decanted from the oil sticking to the walls of the flask, and the oil is then triturated three times with 100 ml. of diethyl ether each time. After removal of the last traces of ether in vacuo, the oil is triturated with 150 ml. of water until it crystallizes. The crystalline residue is then filtered off, washed with water and dried in vacuo over phosphorus pen toxide. 13.2 g. (50 percent yield) of N-cyc1opropyl-N'-methyl- N'-(a-phenylchloracetyl) urea are obtained.
Analysis for c,,H,,N,0,c1 (M.W =266.5)
Calc: C=58.54 percent l-l=5 .63 percent N=l0.50 percent Found: C=58. l 3 percent l-l=5.6l percent N=l0.4l percent 58.42 percent 5.82 percent 10.68 percent b. 5-phenyl-2-(N-cyclopropyl-N-methylarnino)-4-oxalinone 26.6 g. (0.1 g. mole) of N-cyclopropyl-N-methyl-N'-(a-pheny1-a-chloracetyl)urea are dissolved in a solution of sodium ethoxide obtained by dissolving 2.3 g. (0.1 g. atom 1 of sodium in 500 ml. of absolute ethanol, and the mixture is heated for 2 hours under reflux. The sodium chloride produced is filtered off, the alcohol is evaporated from the filtrate on a water bath in vacuo, and the gummy residue is triturated with 250 ml. of water until it crystallizes. The crystalline residue is filtered off, washed with water and dried in vacuo over phosphorus pentoxide. 15.1 g. (60 percent yield) of S-phenyl-Z-(N- cyclopropyl-N-metl'iylamino)-methylamlno)-4-oxazolinone are obtained. After recrystallization from a mixture of ethyl acetate and hexane (2:3), it melts at C. Analysis for C, H N O, (M.W.=230) Calc. C=67.83 percent l-l =6.09 percent N=l2.l7 percent Found: C=67 .80 percent l-l=6.13 percent N=1 1.95 percent 67.61 percent 6.28 percent 12.20 percent The ultraviolet absorption spectrum shows Amax. C,H,OH= 230 1,. e=28,000v
k increase in motor activity with reference 10 the controls 30 minutes alter 60 minutes after Dose (mg/kg.) administration administration In equal doses, d-amphetamine provokes essentially the same motor hyperactivity but is less long-lasting in effect. In addition, amphetamine is a convulsent, unlike the new compounds.
Tests carried out in rats according to the method of A. P. Roszkowski et al. (J. Pharmacol. Exp. Th. 1963, 140, 367) show that the ED 50 of the Z-monocyclopropylamino compound of example 1 and d-amphetamine are very similar, to WIL' d-amphetamine 2.6 mgJkg.
2-monocyc1opropy1amine compound 3.1 mgJkg.
The anorexigenic effect of the compound of example 111 likewise is not significantly different from that of damphetamine. The oral toxicity of this new compound administered orally in the mouse is less than that of damphetamine. This compound has only a very slight cardiovascular effect in the cat or dog in doses up to 5 mgjkg. ad ministered parenterally.
The toxicity of the 5-phenyl-2-monocyclopropylaminc-4- oxazolinone is low in comparison with the activity thereof. Thus, while said activity was found to be four to five times greater than that of 5-phenyl-2-monoethylamino-4-oxazolinone (the most potent compound per os in the group of Z-monoalkylamino and Z-dimethylamino compounds), the respective lethal doses (LD 50) are S-phenyl-Z-monovth ylamino-4-0xaz0liu0ne. G./kg. Intraporitonoal routt- 0. Subcutaneous rouu- U. 340
5-phenyl-2-monocyclo iro 1vlamino-4-oxaz0liu0ue Intraperitoueal route 0. 081 Subcutaneous route. 0. 142
Thus while the Z-cyclopropylamino compound is four to five times more active than the Z-monoethylamino compound, the toxicity of the first one is only 2.5 times greater than that of the second one, ie has a therapeutic index about twice better.
These new -phenyl-2-cyclopropylamino-4-oxazolinones may be employed for therapeutic purposes:
I. As a psychotonic drug:
in depressive states having various causes, to combat physical and mental asthenia and to increase the psychic tonus and the power of concentration and attention:
in states in which anxiety with inhibition constitutes a dominant symptom, to produce the reappearance of spirit" with the resumption of rational activity and the power to analyze facts logically.
ll. As an antifatigue" agent by means of which it is possible to postpone the hour of normal sleep without inhibiting sleep on retiring to bed.
[11. As an anorexigenic.
The invention includes within its scope pharmaceutical compositions comprising a compound of formula I in associa tion with a compatible pharmaceutically acceptable diluent or carrier, and preferably in a form suitable for oral administration. Each unit dose should contain an amount of active ingredient such that a daily dose of l to l,000 mg. of active substance can be spread over two to four unit doses. For the compound of example Ill, a daily dose of l to 50 mg. in unit doses each containing 1 to mg. is generally suitable. The compound of example I may be administered orally in the form of tablets containing from 1 to 30 mg. of active substance; a daily dosage of from 1 to about mg. being preferred where the production of anorexic effects is to be sought, while higher dosages, eg about 15 to about 60 mg, are preferably adopted where stimulation of the central nervous system is particularly sought.
An example of a composition for a tablet is as follows:
5-phenyl-2-cyclopropylaminod-oxazolinone 0.001 g. Lactose 0.0635 g. Corn starch 0.008 g. Tricalcium phosphate 0.025 g, Orange yellow S 0.0005 g. Magnesium stearate 0.002 g.
Particularly advantageous forms of oral administration of the new compounds are provided by S-phenyl-Z- cyclopropylamino-4-oxazolinone fixed on certain pharmaceutically acceptable synthetic resins of the cation exchange resin type, for example cation exchange resins containing sulfonic groups, a suitable one being Amberlite IR. 120 {H} Such a resin with the 5-phenyl-2-cyclopropylamino- 4-oxazolinone fixed thereon may be depicted as an acid addition salt which may be termed a resinate."
An advantage of such a resinate" is that the new amine is gradually liberated therefrom in the organism after it has been administered. Hence the therapeutic action is protracted and the total daily dosage of drug may be administered at one go, a point believed particularly important as the new compound is anorexigenic to a considerable degree.
with a view to preparing such a resignate," a solution of S- phenyl-2-cyclopropylamino-4-oxazolinone may be passed through a column or bed of the cation exchange resin until the 5-phenyl-2-cyclopropylamino-t-oxazolinone content in the effluent is the same as in the feed; the proportion of oxazolinone compound thus fixed varies according to the cation exchange resin.
The resinates" are preferably encapsuled, e.g. in conventional gelatin capsules containing l to 60 mg. of 5-phenyl-2- cyclopropylamino-t-oxazolinone. For example, one capsule may contain 5 mg. of said oxazdinone fixed on the required amount of Amberlite LR. [l-l} for saturation with said oxazolinone.
It should be understood, of course, that the foregoing disclosure relates only to preferred embodiments of the invention and that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purposes of the disclosure which do not constitute departures from the spirit and scope of the invention.
We claim:
1. A compound of the formula and the nontoxic acid addition salts thereof. 2. A method for producing the compound of the formula C CH;
which comprises heating to reflux temperature in a lower aliphatic alcohol medium a mixture of sodium ethoxide with an equimolecular amount of a urea of the formula wherein hal is halogen, to cyclize said urea.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2892753A (en) * | 1957-02-26 | 1959-06-30 | Boehringer Sohn Ingelheim | Central nervous system stimulant |
US3029189A (en) * | 1962-04-10 | S-aryl-z-mno-x-qxazolibinones | ||
US3037990A (en) * | 1961-01-10 | 1962-06-05 | American Cyanamid Co | Process for preparing 5-phenyl-2-dialkylamino-2-oxazolin-4-ones |
US3047461A (en) * | 1960-06-10 | 1962-07-31 | American Cyanamid Co | Central nervous system stimulant |
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1967
- 1967-07-21 US US655002A patent/US3609159A/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US3029189A (en) * | 1962-04-10 | S-aryl-z-mno-x-qxazolibinones | ||
US2892753A (en) * | 1957-02-26 | 1959-06-30 | Boehringer Sohn Ingelheim | Central nervous system stimulant |
US3047461A (en) * | 1960-06-10 | 1962-07-31 | American Cyanamid Co | Central nervous system stimulant |
US3037990A (en) * | 1961-01-10 | 1962-06-05 | American Cyanamid Co | Process for preparing 5-phenyl-2-dialkylamino-2-oxazolin-4-ones |
Non-Patent Citations (1)
Title |
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Najer et al., Bull. Soc. Chim. France, Ser. 5, pages 1810 1813 (1963). * |
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